Targeting and regulation of reactive oxygen species generation by Nox family NADPH oxidases.
Targeting and regulation of reactive oxygen species generation by Nox family NADPH oxidases.
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DOI：
10.1089/ars.2009.2637
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发表时间：
2009-10
影响因子：
6.6
通讯作者：
Ueyama T
中科院分区：
文献类型：
--
作者：
Leto TL;Morand S;Hurt D;Ueyama T
Nox 家族 NADPH 氧化酶具有多种需要产生活性氧 (ROS) 的功能，包括抗菌防御、生物合成过程、氧传感和基于氧化还原的细胞信号传导。我们探索了几种 Nox 家族氧化酶的靶向、组装和激活，因为 ROS 的产生似乎在空间和时间上都受到调节。 Nox1 和 Nox3 与吞噬细胞（基于 Nox2）氧化酶类似，充当产生超氧化物的多组分酶。调节其活性的因素包括胞质激活剂和组织蛋白以及 GTP-Rac。它们的调节各不相同，顺序如下：Nox2>Nox1>Nox3。亚细胞靶向的决定因素包括：1) 形成允许质膜易位的 Nox-p22phox 异二聚体复合物，2) 包含 PX 结构域的组织者蛋白（p47phox 或 Nox 组织者 1 (Noxo1)）的磷脂结合特异性，以及 3）Noxo1 PX 结构域的可变剪接，将其引导至细胞核或血浆 膜。双氧化酶（Duox1 和 Duox2）具有不同的机制。质膜靶向导致 H2O2 释放，而不是超氧化物，以支持细胞外过氧化物酶。人类 Duox1 和 Duox2 没有明显的过氧化物酶活性，尽管它们与血红素过氧化物酶具有广泛的同源性。双氧化酶由 Duox 激活剂 2 (Duoxa2) 或两个 Duoxa1 变体重建，它们决定成熟、亚细胞定位以及通过与 Duox 形成稳定复合物产生的 ROS 类型。
Nox family NADPH oxidases serve a variety of functions requiring reactive oxygen species (ROS) generation, including antimicrobial defense, biosynthetic processes, oxygen sensing and redox-based cellular signaling. We explored targeting, assembly, and activation of several Nox family oxidases, since ROS production appears to be regulated both spatially and temporally. Nox1 and Nox3 are similar to the phagocytic (Nox2-based) oxidase, functioning as superoxide-generating multi-component enzymes. Factors regulating their activities include cytosolic activator and organizer proteins and GTP-Rac. Their regulation varies, with the following rank order: Nox2>Nox1>Nox3. Determinants of subcellular targeting include: 1) formation of Nox-p22phox heterodimeric complexes allowing plasma membrane translocation, 2) phospholipids-binding specificities of PX domain-containing organizer proteins (p47phox or Nox organizer 1 (Noxo1)), and 3) variably splicing of Noxo1 PX domains directing them to nuclear or plasma membranes. Dual oxidases (Duox1 and Duox2) are targeted by different mechanisms. Plasma membrane targeting results in H2O2 release, not superoxide, to support extracellular peroxidases. Human Duox1 and Duox2 have no demonstrable peroxidase activity, despite their extensive homology with heme peroxidases. The dual oxidases were reconstituted by Duox activator 2 (Duoxa2) or two Duoxa1 variants, which dictate maturation, subcellular localization, and the type of ROS generated by forming stable complexes with Duox.